Tuning the Local Availability of VEGF within Glycosaminoglycan‐Based Hydrogels to Modulate Vascular Endothelial Cell Morphogenesis

Abstract

Incorporation of sulfated glycosaminoglycans (GAGs) into cell-instructive polymer networks is shown to be instrumental in controlling the diffusivity and activity of growth factors. However, a subtle balance between local retention and release of the factors is needed to effectively direct cell fate decisions. To quantitatively unravel material characteristics governing these key features, the GAG content and the GAG sulfation pattern of star-shaped poly(ethylene glycol) (starPEG)-GAG hydrogels are herein tuned to control the local availability and bioactivity of GAG-affine vascular endothelial growth factor (VEGF165). Hydrogels containing varying concentrations of heparin or heparin derivatives with different sulfation pattern are prepared and thoroughly characterized for swelling, mechanical properties, and growth factor transport. Mathematical models are developed to predict the local concentration and spatial distribution of free and bound VEGF165 within the gel matrices. The results of simulation and experimental studies concordantly reveal how the GAG concentration and sulfation pattern determine the local availability of VEGF165 within the cell-instructive hydrogels and how the factor-in interplay with cell-instructive gel properties-determines the formation and spatial organization of capillary networks of embedded human vascular endothelial cells. Taken together, this study exemplifies how mathematical modeling and rational hydrogel design can be combined to pave the way for precision tissue engineering.

Injectable Glycosaminoglycan-Based Cryogels from Well-Defined Microscale Templates for Local Growth Factor Delivery

“…If faster NGF release would be required, the heparin could first be subjected to selective desulfation procedures, to remove some of the sulfate groups allowing quicker protein release. 35 − 37 …”

Biomaterials for protein delivery for complex tissue healing responses

“…63 Heparin binding proteins bind reversibly to biomaterials containing sulphated GAGs (heparin 10,64,65 and chondroitin sulphate 66,67 ), non-sulphated GAGs such as hyaluronic acid, [68][69][70] other natural polysaccharides derived from plants and animals (alginate 71 and chitosan 72,73 ), and combinations of these polymers. [74][75][76] Sulphated GAG-based biomaterials interact with a variety of protein partners (heparan sulphate to FGF-2, VEGF-A165, and SDF-1α; 65,77 heparin to BMP-2; 78,79 chondroitin sulphate to TGF-β1 and BMPs 66 ). The abundance of heparin and heparan sulphate in both normal and injured tissues strongly suggests that supplementation with GAGbased biomaterials may improve the efficacy of a protein therapy.…”

“…62 However, the protein binding properties of GAG-based, electrostatically-driven biomaterials can be tuned by modifying their sulphate content, which changes the electrostatic interactions between the protein and material and subsequently alters protein release from the material. 70,77,[81][82][83] Sulphating non-sulphated molecules such as hyaluronic acid and alginate increases protein retention, while desulphating GAGs such as heparin increases protein release. Sulphation of hyaluronic acid can also slow biomaterial degradation by reducing the availability of octosaccharides necessary for effective degradation by the enzyme hyaluronidase.…”

“…[187][188][189] Additionally, we and others have employed computational bio-transport models to predict protein release kinetics from biomaterials and tune biomaterial properties to achieve desired release rates in vitro and in vivo. 10,64,77 Limasale et al demonstrated that a reaction-diffusion model could be used to predict the effect of heparin content and sulphation pattern on VEGF release, as well as the spatial distribution of VEGF throughout the hydrogel. Collectively, these examples demonstrate the value of high throughput screening technologies and computational modelling for the rational design of biomaterials for tissue engineering applications.…”

Natural Glycan Derived Biomaterials for Inflammation Targeted Drug Delivery

“…recently report the rational design of heparin‐derived hydrogels to control the local availability of vascular endothelial growth factors (VEGF165). [ 105 ] Specifically, the thiol‐functionalized starPEG, and the maleimide functionalized heparin (HP) were covalently conjugated via orthogonal Michael‐type addition. The concentration of HP and its sulfation pattern were proven critical in determining the release behavior of VEGF165, i.e., the higher the HP concentration, the lower the diffusivity of VEGF165 due to higher affinity between VEGF165 and HP.…”